scholarly journals Paracellular bicarbonate flux across human cystic fibrosis airway epithelia tempers changes in airway surface liquid pH

2020 ◽  
Vol 598 (19) ◽  
pp. 4307-4320 ◽  
Author(s):  
Ian M. Thornell ◽  
Tayyab Rehman ◽  
Alejandro A. Pezzulo ◽  
Michael J. Welsh
Keyword(s):  
Cystic Fibrosis ◽  
Airway Surface Liquid ◽  
Airway Epithelia ◽  
Cystic Fibrosis Airway ◽  
Surface Liquid

scholarly journals Small Molecule Anion Carriers Correct Abnormal Airway Surface Liquid Properties in Cystic Fibrosis Airway Epithelia

2020 ◽  
Vol 21 (4) ◽  
pp. 1488 ◽  
Author(s):  
Ambra Gianotti ◽  
Valeria Capurro ◽  
Livia Delpiano ◽  
Marcin Mielczarek ◽  
María García-Valverde ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Fluid Composition ◽  
Airway Surface Liquid ◽  
Airway Epithelia ◽  
Drug Candidates ◽  
Cystic Fibrosis Airway ◽  
Functional Models ◽  
Cftr Protein ◽  
Surface Liquid

Cystic fibrosis (CF) is a genetic disease characterized by the lack of cystic fibrosis transmembrane conductance regulator (CFTR) protein expressed in epithelial cells. The resulting defective chloride and bicarbonate secretion and imbalance of the transepithelial homeostasis lead to abnormal airway surface liquid (ASL) composition and properties. The reduced ASL volume impairs ciliary beating with the consequent accumulation of sticky mucus. This situation prevents the normal mucociliary clearance, favouring the survival and proliferation of bacteria and contributing to the genesis of CF lung disease. Here, we have explored the potential of small molecules capable of facilitating the transmembrane transport of chloride and bicarbonate in order to replace the defective transport activity elicited by CFTR in CF airway epithelia. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of our compounds on some key properties of ASL. The treatment of these functional models with non-toxic doses of the synthetic anionophores improved the periciliary fluid composition, reducing the fluid re-absorption, correcting the ASL pH and reducing the viscosity of the mucus, thus representing promising drug candidates for CF therapy.

scholarly journals Lipoxin A4 Stimulates Calcium-Activated Chloride Currents and Increases Airway Surface Liquid Height in Normal and Cystic Fibrosis Airway Epithelia

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e37746 ◽  
Author(s):  
Valia Verrière ◽  
Gerard Higgins ◽  
Mazen Al-Alawi ◽  
Richard W. Costello ◽  
Paul McNally ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Airway Surface Liquid ◽  
Lipoxin A4 ◽  
Airway Epithelia ◽  
Chloride Currents ◽  
Liquid Height ◽  
Cystic Fibrosis Airway ◽  
Surface Liquid

scholarly journals Inhibition of ATP hydrolysis restores airway surface liquid production in cystic fibrosis airway epithelia

2020 ◽  
Vol 318 (2) ◽  
pp. L356-L365 ◽  
Author(s):  
Catharina van Heusden ◽  
Brian Button ◽  
Wayne H. Anderson ◽  
Agathe Ceppe ◽  
Lisa C. Morton ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Steady State ◽  
Atp Hydrolysis ◽  
Fluid Secretion ◽  
Pathological Feature ◽  
Airway Surface Liquid ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Atp Levels ◽  
Surface Liquid

Airway surface dehydration is a pathological feature of cystic fibrosis (CF) lung disease. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated Cl− channel controlled in part by the adenosine A2B receptor. An alternative CFTR-independent mechanism of fluid secretion is regulated by ATP via the P2Y2 receptor (P2Y2R) that activates Ca2+-regulated Cl− channels (CaCC/TMEM16) and inhibits Na+ absorption. However, due to rapid ATP hydrolysis, steady-state ATP levels in CF airway surface liquid (ASL) are inadequate to maintain P2Y2R-mediated fluid secretion. Therefore, inhibiting airway epithelial ecto-ATPases to increase ASL ATP levels constitutes a strategy to restore airway surface hydration in CF. Using [γ32P]ATP as radiotracer, we assessed the effect of a series of ATPase inhibitory compounds on the stability of physiologically occurring ATP concentrations. We identified the polyoxometalate [Co4(H2O)2(PW9O34)2]10− (POM-5) as the most potent and effective ecto-ATPase inhibitor in CF airway epithelial cells. POM-5 caused long-lasting inhibition of ATP hydrolysis in airway epithelia, which was reversible upon removal of the inhibitor. Importantly, POM-5 markedly enhanced steady-state levels of released ATP, promoting increased ASL volume in CF cell surfaces. These results provide proof of concept for ecto-ATPase inhibitors as therapeutic agents to restore hydration of CF airway surfaces. As a test of this notion, cell-free sputum supernatants from CF subjects were studied and found to have abnormally elevated ATPase activity, which was markedly inhibited by POM-5.

Airway Surface Liquid Calcium Modulates Chloride Permeability in the Cystic Fibrosis Airway

2003 ◽  
Vol 168 (10) ◽  
pp. 1223-1226 ◽  
Author(s):  
Peter G. Middleton ◽  
Katy A. Pollard ◽  
Elizabeth Donohoo ◽  
John R. Wheatley ◽  
Duncan M. Geddes ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Airway Surface Liquid ◽  
Chloride Permeability ◽  
Cystic Fibrosis Airway ◽  
Liquid Calcium ◽  
Surface Liquid

scholarly journals Soluble Mediators, Not Cilia, Determine Airway Surface Liquid Volume in Normal and Cystic Fibrosis Superficial Airway Epithelia

2006 ◽  
Vol 127 (5) ◽  
pp. 591-604 ◽  
Author(s):  
Robert Tarran ◽  
Laura Trout ◽  
Scott H. Donaldson ◽  
Richard C. Boucher
Keyword(s):  
Cystic Fibrosis ◽  
Volume Regulation ◽  
Liquid Volume ◽  
Airway Surface Liquid ◽  
Airway Epithelia ◽  
Innate Defense ◽  
Cl Secretion ◽  
Immotile Cilia ◽  
Glandular Secretion ◽  
Surface Liquid

A key aspect of the lung's innate defense system is the ability of the superficial epithelium to regulate airway surface liquid (ASL) volume to maintain a 7-μm periciliary liquid layer (PCL), which is required for cilia to beat and produce mucus flow. The mechanisms whereby airway epithelia regulate ASL height to ≥7 μm are poorly understood. Using bumetanide as an inhibitor of Cl− secretion, and nystatin as an activator of Na+ absorption, we found that a coordinated “blending” of both Cl− secretion and Na+ absorption must occur to effect ASL volume homeostasis. We then investigated how ASL volume status is regulated by the underlying epithelia. Cilia were not critical to this process as (a) ASL volume was normal in cultures from patients with primary ciliary dyskinesia with immotile cilia, and (b) in normal cultures that had not yet undergone ciliogenesis. However, we found that maneuvers that mimic deposition of excess ASL onto the proximal airways, which occurs during mucociliary clearance and after glandular secretion, acutely stimulated Na+ absorption, suggesting that volume regulation was sensitive to changes in concentrations of soluble mediators in the ASL rather than alterations in ciliary beating. To investigate this hypothesis further, we added potential “soluble mediators” to the ASL. ASL volume regulation was sensitive to a channel-activating protein (CAP; trypsin) and a CAP inhibitor (aprotinin), which regulated Na+ absorption via changes in epithelial Na+ channel (ENaC) activity in both normal and cystic fibrosis cultures. ATP was also found to acutely regulate ASL volume by inducing secretion in normal and cystic fibrosis (CF) cultures, while its metabolite adenosine (ADO) evoked secretion in normal cultures but stimulated absorption in CF cultures. Interestingly, the amount of ASL/Cl− secretion elicited by ATP/ADO was influenced by the level of CAP-induced Na+ absorption, suggesting that there are important interactions between the soluble regulators which finely tune ASL volume.

scholarly journals Measuring Airway Surface Liquid Depth in Ex Vivo Mouse Airways by X-Ray Imaging for the Assessment of Cystic Fibrosis Airway Therapies

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e55822 ◽  
Author(s):  
Kaye S. Morgan ◽  
Martin Donnelley ◽  
David M. Paganin ◽  
Andreas Fouras ◽  
Naoto Yagi ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Ex Vivo ◽  
Airway Surface Liquid ◽  
X Ray ◽  
X Ray Imaging ◽  
Cystic Fibrosis Airway ◽  
Liquid Depth ◽  
Surface Liquid

scholarly journals Normal and Cystic Fibrosis Airway Surface Liquid Homeostasis

2005 ◽  
Vol 280 (42) ◽  
pp. 35751-35759 ◽  
Author(s):  
Robert Tarran ◽  
Brian Button ◽  
Maryse Picher ◽  
Anthony M. Paradiso ◽  
Carla M. Ribeiro ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Airway Surface Liquid ◽  
Cystic Fibrosis Airway ◽  
Surface Liquid
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